Novel Approaches in Drug Designing & Development - Juniper Publishers
Vitamin D is one of the most effective vitamins in
the body on the nervous system and cardiovascular system. Its deficiency
can be life threatening. Vitamin D deficiency is associated with
Adiponectin, LDL, TG, VLDL, HDL. Vitamin D deficiency in the elderly can
lead to forgetfulness, depression and mental health problems. In this
article, we have a brief and practical overview of the effects of
vitamin D on the nervous system and cardiovascular system.
Keywords: Vitamin D deficiency; Cardiovascular system; Nervous system; Blood pressure, Lipoprotein
Abbreviations: CVD:
Cardiovascular Disease; CKD: Chronic Kidney Disease; IHD: Ischemic Heart
Disease; BP: Blood Pressure; AF: Atrial Fibrillation; TG: Triglyceride;
LDL: Low density lipoprotein; VLDL: Very Low-Density Lipoprotein; HDL:
High Density Lipoprotein; HCY: Homocysteine; HbA1c: Hemoglobin A1c
(glycated hemoglobin); VDR: Vitamin D Receptor; SNP: Single Nucleotide
Polymorphism; CCA-IMT: Common Carotid Intimal Medial Thickness; hsCRP:
High Sensitivity C-Reactive Protein; PTH: Parathyroid Hormone; MI:
Myocardial Infarction; HF: Heart Failure; CRP: C-Reactive Protein; IL:
Interleukin; CHD: Coronary Heart Disease; SCD: Sudden Cardiac Death;
CAC: Coronary Artery Calcification; SBP: Systolic Blood Pressure; LV:
Left Ventricular; UVB: Ultraviolet-B; TC: Total Cholesterol; MPV: Mean
Platelet Volume; ERI: Erythropoietin Resistance Index; FMD: Flow
Mediated Dilation; AIX: Augmentation index; SEVR: Sub Endocardial
Viability Ratio; PWV: Pulse Wave Velocity; RHI: Reactive Hyperemia
Index; DRDD2 : Dopamine Receptor D2; MS : Multiple Sclerosis; MS NAWM :
MS Normal-Appearing White Matter; ADHD: Attention Deficit Hyperactivity
Disorder; MMSE: Mini-Mental State Examination; NAD: Non-Alzheimer
Dementia
To date, much research has been done on the
mechanism and tissues of the effect of vitamin D, and many experts
emphasize on maintaining the natural level of this vitamin in the body.
The heart can be severely affected by vitamin D
deficiency, which causes CVD. People with CKD are more likely to develop
cardiovascular disease, which researchers believe can help reduce
vitamin D intake [1]. Epidemiological findings indicate an increase in
mortality due to IHD and BP in patients who are further away from the
equator and less exposed to sunlight, resulting in less vitamin D
synthesis in their body [2]. Vitamin D deficiency can be treated with
Non-Valvular AF [3] and correlation of flow in the coronary arteries
[4].
Normal levels of vitamin D are important for the
nervous system. Vitamin D deficiency can cause various cancers,
including
glioma [5]. Vitamin D deficiency has been reported in pregnant women
taking anticonvulsant drugs. Also, the percentage of
autism in these mothers’ infants is higher than others [6]. People
with migraines should pay attention to their poor vitamin D levels
because its deficiency can be one of the causes of migraines [7].
The skin as a tissue is very important in direct
contact with vitamin D. Vitamin D can prevent psoriasis [8]. Extensive
research has been conducted on women and men in the United States. The
study showed that there was no significant relationship between vitamin D
levels and skin cancer as expected [9]. It should be noted that obese
people receive less vitamin D [10], which is more exposed to skin risks
due to deficiency of this vitamin.
Some studies on the effect of vitamin D deficiency on CVD
have linked this to race. [11,12] For example, an increase in BP in
vitamin D deficiency in blacks is half that of whites. [13] Studies
have also been performed on gender. Vitamin D intake in men
was associated with a reduced risk of CVD, although this was not
observed in women [14].
Vitamin D deficiency is associated with obesity [15] and
increased TG [16,17] LDL [18], VLDL [19]. However, other studies
show these results to be random [10,20-24]. Therefore, vitamin D
is associated with the regulation of atherogenic fats and primary
markers of CVD [25].
VDR is expressed throughout the vascular system. The
calcitriol-VDR complex prevents the proliferation of vascular
smooth muscle cells, reduces coagulation, and has antiinflammatory
properties. [26] Organic changes in VDR are
associated with vitamin D deficiency and are more common in
bb genotypes than genotypes. Bb and BB are more deficient in
vitamin D in Bsml SNP gene and aa genotype than Aa and AA
genotypes in Apal SNP gene [27].
Vitamin D deficiency in patients with CKD is associated with
inflammation [28] and albuminuria [29]. Patients with CKD have
higher levels of CCA-IMT, hsCRP, and CD4 + CD28 + null cells, and
there is a strong inverse association between low levels of vitamin
D in these patients and increased factors. It has been reported to
be the cause of atherosclerosis in these patients [30].
Vitamin D levels are inversely proportional to PTH levels [31].
Patients with higher PTH levels are at higher risk for CVD, and
vitamin D deficiency with secondary hyperparathyroidism can
cause CVD [32]. But it was not related to HF but was the opposite
in PTH [33]. In some other studies, unlike PTH, vitamin D was not
associated with CVD [34].
Severe vitamin D deficiency with high CRP causes CVD, but this
effect is not seen for vitamin D alone. Therefore, the association
between vitamin D and CVD depends on the inflammatory status
[35]. Vitamin D itself plays a role in inflammation with a slight
decrease in IL-6 [36]. Vitamins affect the activity and expression
of macrophages and lymphocytes in atherosclerotic plaques and
cause chronic inflammation of the arterial wall [37].
Vitamin D deficiency is an independent predictor of
cardiovascular mortality in ACS patients [38]. Vitamin D
deficiency is associated with an increased risk of CAD (not its
prevalence) [39] and individuals with vitamin D deficiency
are more likely to have coronary artery disease [40]. Vitamin D
deficiency is associated with increased risk of HF [41-43], CHD
[44], MI [45,46], aortic calcification [47] SCD [48], CAC [49]
as well as increased SBP [50]. The effect of vitamin D on IHD
[51,52] and AF [53,54] is contradictory. No association was found
between vitamin D deficiency and LV diastolic dysfunction and
only a slight association was found between vitamin deficiency
and interventricular septal thickness [55]. Vitamin D CHD had no
effect on secondary cardiovascular events [56].
In patients with metabolic syndrome, the risk of cardiovascular
factors increases [57] and vitamin D deficiency is associated with
metabolic syndrome [58]. UVB radiation has also been shown
to reduce type 2 diabetes by increasing vitamin D levels [59].
However, no other study has shown an association between
vitamin D and diabetes [60]. Studies in diabetic patients with
vitamin D deficiency have shown weight gain, TC and TG [61]
Vitamin D deficiency in these patients was also associated with
increased BP and HbA1c. [62] The higher risk of CVD due to
vitamin D deficiency in diabetic patients may be due to inadequate
heart regeneration.
Vitamin D has an inverse relationship with MPV [63] and ERI
[64] and a direct relationship with hemoglobin [65]. Also, vitamin
D deficiency causes less FMD and thus causes Vascular endothelial
dysfunction [66,67]. Vitamin D deficiency with arterial stiffness
indices (AIX, SEVR, PWV) and arterial function branches (FMD,
RHI). Vitamin D deficiency was associated with less SEVR, FMD,
and RHI, and more AIX and PWV [68,69]. And an abdomen [70]. The real relationship between the effect of vitamin D and CVD
is difficult. One of the reasons for the effect of CVD risk factors on
serum vitamin D concentration. For example, weight loss reduces
cardiovascular risk factors and at the same time increases the
concentration of vitamin D due to reduced fat mass [71]. Some studies have not found vitamin D to be associated
with CVD [72]. Other studies have found that vitamin D
supplementation has no effect on CVD [73-75]. Other studies have
found that vitamin D supplementation has an effect on CVD only
in people with vitamin D deficiency. It is considered ineffective in
people with normal serum levels of vitamin D [76].
Serum levels of vitamin D are generally measured at
serum
levels of 25 (OH) D. The borderline level for vitamin D is 56 nmol
/ L in women but 50 nmol / L in men. Serum levels of Caucasians
are higher than serum levels of vitamin D in other breeds.
Latitude has no significant effect on serum levels of vitamin D;
But the culture of the people of each region is effective based on
the way of covering and feeding on their serum vitamin D level
[77]. Vitamin D levels in summer compared to winter, younger
ages (50-70 years) than older ages (70-87 years), women are
different from men, but serum vitamin D levels do not depend on
BMI [78]. The use of vitamin D supplements at different ages has
different effects on the psychological level of people. The use of
vitamin D supplements has no effect on the mental and emotional
functioning of adolescents [79]. Taking vitamin D supplements
has no effect on mental function and memory in middle-aged
people; However, the use of vitamin D supplements and high
serum levels of vitamin 25 (OH) D, in aging, has a significant effect on
reducing the risk of Alzheimer’s disease and dementia. In older
people with higher serum levels of 25 (OH) D, they perform better
at remembering words than older people with lower levels of 25
(OH) D, but higher levels of 25 (OH) D in speaking fluently have
mental performance. And the depressive state of the elderly has
no effect. Elderly people with lower serum levels of 25 (OH) D are
more likely to develop amnesia [80]. Vitamin D deficiency affects
the genes of mitochondrial, cytoskeletal and synaptic proteins
by affecting the genes of intracellular processes and intercell
synapses in the brains of adult mice [81]. Taking vitamin D
supplements in middle age improves short-term memory but has
no effect on the memory factor associated with semantic memory
[82].
Among older men and women, people with lower serum
levels of vitamin D have slower reaction time, lower endurance,
slower gait, and poorer performance-related performance and
visual-spatial performance tests. There was no difference in
the number of falls between the elderly in the two groups with
sufficient serum vitamin D levels and the group with vitamin D
deficiency [83]. Elderly people who do not have dementia but
have MCI have lower serum concentrations of vitamin D than a
group of mentally healthy elderly people. People with higher
levels of serum vitamin D are less likely to develop MCI (MCI: Mild
Cognitive Impairment) [84]. In the elderly, vitamin D deficiency
is seen, as a result of which the brain activities of these people,
especially in the field of spatial memory, are less efficient than
their peers with sufficient levels of vitamin D [85]. In a group of
mice deficient in vitamin D, they had a lower pain threshold than
in a control group that received a sufficient vitamin D diet. Vitamin
D receptor expression increased at the time of spinal cord injury in
both groups, while, as expected, serum 25 (OH) D did not change
[86]. Taking vitamin D supplements if the serum concentration of
vitamin D is between 50-80 ng / ml, improves sleep; If the serum
concentration of vitamin D is more than 80 or less than 50 ng per
ml, it can cause sleep disorders [87].
The effect of taking vitamin D supplements is that with a 10-
fold increase in the dose of vitamin D, the serum concentration of
25 (OH) D doubles. In the hippocampus of mice with high serum
vitamin D levels, the expression of genes involved in cellular
communication, synaptic translocation, and G protein-coupled
receptor activity is increased [88]. Vitamin D has improved the symptoms of patients with
irritable bowel syndrome by affecting the peripheral nervous
system, inflammatory processes, and on the other hand, by
affecting the central nervous system, the level of anxiety in
individuals [89]. Increased expression of vitamin D receptors increases
dopamine synthesis by affecting the gene responsible for dopamine
packaging and protection; Vitamin D increases dopamine by
reducing the expression of DRD2 gene [90].
Vitamin D does not affect the severity of stroke. Vitamin D has
an effect on IGF-I, which acts as a neuroprotectant in the stroke
ward and improves the post-stroke process [91].
The use of vitamin D supplements in people with migraines
reduces the frequency of migraine headaches and the effects that
migraine headaches have on the course of life. In people treated
with vitamin D supplements, CGRP levels (an important peptide
that is higher in people with migraine headaches than in others)
were lower than in controls [92].
Numerous results have been obtained in the study of the effect
of vitamin D deficiency in the fetal period, from which the opposite
can be mentioned. In mice deficient in vitamin D, the interval
between bregma and lambda and tyrosine hydroxylase levels,
which are involved in the synthesis of dopamine by dopaminergic
and adrenergic neurons, is lower than normal due to low tyrosine
hydroxylase levels. The number of dopaminergic neurons in
the substantia nigra and part of the tegmentum decreases [93].
Mice that were deficient in vitamin D during pregnancy had the
same learning as mice that received normal levels of vitamin
D during pregnancy, but between 30 and 70 weeks after birth,
the hippocampus of the group that received vitamin D during
pregnancy They were deficient in vitamin D, had a greater
reduction in volume than the other group, and at 30 weeks after
birth had a smaller volume of cerebral ventricles than the other
group, which disappeared at 70 weeks [94]. Vitamin D deficiency
in the fetus leads to changes in the amount of neurotransmitters
in different parts of the brain such as increased dopamine,
increased noradrenaline in the hippocampus and thalamus and
hypothalamus and midbrain, decreased serotonin in the basal
ganglia and caudate and putamen, decreased glutamine and
glutamate in Different parts of the brain and the increase in serine,
glycine and taurine occur only in limited parts of the brain [95].
In female mice deficient in vitamin D, an increase in dopamine
transporters is seen in the Putamen, Caudate, and Nucleus
accumbens parts of the brain; While there is no difference in
other receptors and neurotransmitters in other parts of the
brain between mice with normal vitamin D levels and vitamin D
deficiency [96].
1-alpha hydroxylase is one of the enzymes that
converts
vitamins into active forms in the brain. Expression of this enzyme
is found only in the cytoplasm of nerve cells and glia. Vitamin D
receptors are present almost exclusively in the nucleus of nerve
cells and glia and are not present in the cytoplasm of these cells.
Most of the vitamin D receptors are found in the superficial
granular layer of the prefrontal part of the cerebral cortex, but in
the molecular layer of the prefrontal part of the cerebral cortex.
The enzyme 1-alpha hydroxylase is found in greater amounts in
the molecular layer of the cerebral cortex and in the superficial
granular layer. In the molecular part of the cingulate gingiva, there
is a relatively large amount of vitamin D receptors. None of the
amygdala parts have a receptor for vitamin D, and the enzyme
1-alpha hydroxylase is moderately expressed in the amygdala. All
thalamic nuclei have small or moderate amounts of vitamin D and 1-alpha
hydroxylase receptors, but are abundant in the supraoptic
and paraventricular nuclei of the hypothalamus, especially in large
cells. Vitamin D receptors are not present in the molecular and
porcine layers of the cerebellum, but are abundant in the granular
layer. The enzyme 1-alpha hydroxylase is moderately found in the
molecular layers and cerebellar Purkinje but is either absent or
present in small amounts in many cells of the granular layer [97].
Mutations in the vitamin D receptor gene in mice cause
many changes in behavior, mental function, balance, etc., which
are explained below. Vitamin D can affect balance processes by
affecting muscles. By causing a mutation in the vitamin D receptor
gene and altering the expression of the vitamin D receptor gene
in the balance sections, disturbances in balance at altitude,
swimming in a pool that, like other mice, were unable to swim
vertically [98]. By mutating the vitamin D receptor gene on one of
the mouse chromosomes, the mice did not change their behavior
and acted like mice with two healthy vitamin D receptor genes
[99].
By deleting the vitamin D receptor gene in mice, apoptosis
in various parts of the brain is dramatically reduced; Including
gingival cingulate, dentate, hypothalamic and basal nuclei.
Due to the decrease in apoptosis, the number of mitotic cells in
these areas increases [100]. vidra and vdrb are two paralogs of
vitamin D receptors. In zebrafish, vdrb was removed in larvae by
MO injection, which resulted in the removal of Meckel cartilage
and palatoquadrate, as well as cartilage hypoplasia. By removing
both vdra and vdrb by MO injection, removal of cartilaginous
structures of the cranial-series was seen. These findings suggest
that VDR expression and signaling are involved in the formation of
cranial-serial muscles [101]. Mice that were heterozygous for the
lack of the vitamin D receptor gene on one of their chromosomes
(heterozygous) showed the same results in depression tests as
mice that were homozygous for the vitamin D receptor gene (wild
type). Whereas mice homozygously lacked the vitamin D receptor
gene (null mutant) showed more depressive behaviors than the
other two groups in the same tests [102].
Most people with mental health problems are deficient in
vitamin D; Most of these mental problems are in the realm of
timing and semantic memory. Older people who are deficient in
vitamin D are more likely to develop mental illness [103]. The
effect of vitamin D deficiency on mental processes in older mice
is greater than that of vitamin D deficiency in young mice; But
older mice generally had slower reactions than younger mice.
Older mice with normal levels of vitamin D had higher levels of
anti-inflammatory cytokines and lower levels of proinflammatory
cytokines than older mice deficient in vitamin D; However, both
anti-inflammatory and pro-inflammatory cytokines were higher
in older mice than in young mice [104], which have a significant
effect on the course of the disease in MS [105].
24-OHase is one of the genes affecting the expression of
vitamin D receptor, which is most expressed in cerebral cortex
cells and parts of the hypothalamus such as periventricular and
supraoptic nuclei. In glia cells in the brain, vitamin D receptor
expression was seen in both control and MS patients; But in MS
NAWM patients, cytoplasmic vitamin D receptor expression was
seen, which is not present in the control group. Expression of
vitamin D receptors in active affected parts is higher than NAWM.
In fact, it appears that the vitamin D receptor mRNA in the affected
areas was higher than the vitamin D receptor mRNA in the NAWM
MS, which probably indicates the formation of the active 1,25 (OH)
2D form in the affected area and increased tissue response in Has
been equivalent to this metabolite [106].
In people with MS who have been on vitamin D supplementation
for 6 or 12 months and whose serum levels have increased by
50 nmol / L, 57% less than other people have seen an increase
in the number of nerve lesions and a recurrence rate of 27% The
reduction [107] and the volume of T2 lesions [108] were less
during the period and had 0.27% less brain tissue damage [109].
Vitamin D supplementation outside the human body indicates a
decrease in IL-17, but in vivo and in the form of high-dose vitamin
D supplementation in patients with MS, leads to an increase in IL-
17 by 60%. Decreases in IL-17 occur in 40% of individuals, none of
whom showed signs of exacerbation of symptoms [110]. Vitamin
D supplementation increased TGF-Beta in patients with MS, while
there was very little increase in TGF-Beta in the control group. Use
of vitamin D supplements in other cytokines including IL-2, IL-4,
IL-5, IL-6, IL-9, IL-10, IL-13, IL-17A, INF-gamma and TNF -alfa did
not change [111]. Taking high-dose vitamin D supplements over
3 months leads to an increase in serum vitamin D levels, which is
positively correlated between vitamin D supplementation and IL-
10 logarithm [112]. In patients with MS, patients taking vitamin
D supplementation did not experience neurological damage to
the CNS, whereas in the group taking vitamin D supplementation,
neurological damage was observed [113]. The risk of developing
MS depends on the mother’s serum level of vitamin D during
pregnancy; Thus, mothers who have insufficient serum vitamin D
levels during pregnancy and are deficient in vitamin D are more
likely to develop MS in their children. [114] Serum levels of vitamin
D at birth have no effect on the risk of developing MS [115].
The percentage of people with vitamin D deficiency
is highest
in winter and lowest in summer; This is while in winter, people
are more prone to depression than other seasons. Among patients
with depression, the percentage of people who are deficient in
vitamin D or inadequate levels of vitamin D is higher than people
with normal levels of vitamin D. Post-stroke depression is more
common in people with vitamin D deficiency [116]. By placing
patients with depression treated with vitamin D, the rate of
fatigue, insomnia, physical weakness and feelings of depression in
these patients is reduced [117]. A group of people who have been
or are suffering from depression are more likely to be deficient in
vitamin D than the control group, and people with lower serum
levels of vitamin D have experienced longer periods of depression,
which is evidence of the effect of concentration and level. Serum of
vitamin D is on the periods and symptoms of depression [118].
During the 8-week treatment of children with ADHD with
vitamin D supplementation in combination with methylphenidate,
in the experimental group and methylphenidate supplementation
without vitamin D supplementation in the control group, children
who took vitamin D supplementation had fewer symptoms in
the afternoon than They were in the control group, while the
symptoms of morning ADHD were not different between the two
groups [119].
Among Swedes, people with autism have lower levels of
vitamin D than their siblings who do not have autism. People
with autism were more likely to be born in the summer or spring,
which had nothing to do with vitamin D levels [120]. In general,
the serum level of 25 (OH) D in children with autism is lower than
normal, due to which they also have lower serum calcium levels
[121]. The use of vitamin D supplements has had a positive effect
on improving the symptoms of autism in children; Especially if
this supplement is used at a younger age [122]. 2 months after
stopping taking vitamin D supplements, the symptoms of the
disease in these children worsened, and with continued vitamin
D supplementation, their symptoms improved again. In patients
with autism, serum levels of 25 (OH) vitamin D are lower than
normal serum levels. One way to improve the symptoms of autism
is to take vitamin D so that its serum level reaches at least 40 ng /
ml; If the serum level of vitamin D is lower, the therapeutic effects
of vitamin D will not be observed [123].
Taking a daily supplement of 2000 IU in the first year of life
reduces the risk of schizophrenia in men by 77% in adulthood,
but such an effect has not been observed in women and other
mental illnesses [124]. Schizophrenia, treatment with vitamin D
supplementation for 8 weeks, did not change the psychological
symptoms and metabolic parameters compared to the control
group [125] Among people with schizophrenia, patients with
lower levels of vitamin D, more severe negative symptoms and
neurological function - Show a weaker cognition [126]. There is an
inverse relationship between the risk of schizophrenia and fetal
vitamin D levels; Vitamin D deficiency in the fetus increases the
risk of schizophrenia. Surprisingly, people with maximal serum
vitamin D levels during pregnancy are more likely to develop
schizophrenia than fetuses with normal vitamin D serum levels
[127].
People with inadequate vitamin D levels or vitamin D
deficiency are more likely to have dementia, cognitive decline, and
Alzheimer’s disease [128,129]. There is no difference in spatial
learning between mice with Alzheimer’s with a normal diet and
with vitamin D supplementation; However, spatial learning was
poorer in the group of mice with Alzheimer’s disease and on a
diet deficient in vitamin D than in the other groups [130]. Taking
mematine with vitamin D supplements in Alzheimer’s patients
improves their mental abilities in MMSE, while taking mematine
or vitamin D supplement alone does not affect people’s mental
abilities [131].
Older people with a serum level of 25 (OH) D borderline or
lower lip are more likely to develop NAD. The onset of NAD is not
related to the serum level of vitamin D in individuals. (NAD is
actually a mental disorder associated with the destruction of the
subcortical area, of which Parkinson’s is a type of NAD [132].
Serum levels of 25 (OH) D in patients with Parkinson’s and
Alzheimer’s are lower than normal. Serum levels of vitamin D in
patients with Parkinson’s are even lower than serum levels of
vitamin D in patients with Alzheimer’s disease [133].
People with serum levels of 25 (OH) D are lower than normal
levels are more likely to develop Parkinson’s, which is associated
with a higher level of serum (OH) D; Thus, people with a serum
level of vitamin D of 50 nmol / L are 65% less likely to develop
Parkinson’s disease than people with a serum level of vitamin D of
25 nmol / L [134]. There are differences between the genotypes
of people with Parkinson’s disease and healthy people, so that
in patients with Parkinson’s disease, the frequency of CC + CT
replication in the vitamin D receptor gene in Fok1 polymorphism
is higher than in healthy people in Hungary; Due to the change in
the vitamin D receptor gene, it becomes 3 amino acids shorter than
normal and thus affects the structure of the vitamin D receptor
and its function. But there was no difference in vitamin D receptor
gene in Apal, Taql and Bsml [135].
There was no difference in vitamin D receptor gene in Apal
and Taql between healthy people with MS [136].
In patients with epilepsy, vitamin D receptors on cells around
blood vessels were lower than in healthy individuals, which was
accompanied by a deficiency of vitamin D in the serum of patients
with epilepsy [137]. In a group homozygously lacking the vitamin
D receptor gene. Seizures and epileptic seizures are more frequent
than groups that are homozygous for vitamin D receptor gene or
heterozygous for vitamin D receptor gene, which indicates the
effect of vitamin D receptor on epileptic brain-related processes
[138]. Taking vitamin D supplements in people with epilepsy
leads to a 40% reduction in seizures [139].
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